Anticancer activity of small amphipathic β2,2-amino acid derivatives

We report the anticancer activity from screening of a series of synthetic β2,2-amino acid derivatives that were prepared to confirm the pharmacophore model of short cationic antimicrobial peptides with high anti-Staphylococcal activity. The most potent derivatives against human Burkitt's lymphoma (Ramos) cells displayed IC50 values below 8 μM, and low toxicity against human red blood cells (EC50 > 200 μM). A more than 5-fold preference for Ramos cancer cells compared to human lung fibroblasts (MRC-5 cells) was also obtained for the most promising β2,2-amino acid derivative 3-amino-N-(2-aminoethyl)-2,2-bis(naphthalen-2-ylmethyl)propanamide (5c). Screening of 5c at the National Cancer Institute (NCI, USA) confirmed its anticancer potency and revealed a very broad range of anticancer activity with IC50 values of 0.32–3.89 μM against 59 different cancer cell lines. Highest potency was obtained against the colon cancer cell lines, a non-small cell lung cancer, a melanoma, and three leukemia cell lines included in the NCI screening panel. The reported β2,2-amino acid derivatives constitute a promising new class of anticancer agents based on their high anticancer potency, ease of synthesis, mode-of-action, and optimized pharmacokinetic properties compared to much larger antimicrobial peptides.

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► Screening of small synthetic β2,2-amino acids revealed anticancer activity.
► The β2,2-amino acids confined the pharmacophore model of small antimicrobial peptides.
► A lead compound was screened at NCI showing high potency and broad range of activity.
► Offers solutions to pharmacokinetic limitations of larger anticancer peptides.